The purpose of these studies is to define the cellular and genetic mechanisms involved in the induction of autoimmunity using an animal model of experimental autoimmune thyroiditis (EAT). We recently developed a system in which severe lesions of EAT can be transferred to normal mice with thyroglobulin (TG) - sensitized T lymphocytes which were activated in vitro with antigen. The increased manipulative capacity of this cell transfer model will enable us to ask many important questions concerning the cellular events involved in the induction and regulation of EAT which could not be approached using intact actively immunized animals. With this model it is possible to separate three distinct stages in the pathogenesis of EAT: 1) the initial in vivo immunization which results in priming of effector cell precursors, 2) the in vitro step in which these sensitized precursors are activated to become T cells that can transfer EAT and 3) the process by which these activated T cells induce EAT after transfer to recipient mice. Specifically, we will determine the cell-cell interactions which are involved both in the initial sensitization of effector cell precursors and in the in vitro activation of precursors to active effector cells. The major focus of our studies will be the mechanisms involved in the in vitro activation step since this is the one which can be most readily manipulated. Activated T cells will be grown as cell lines and cloned in order to determine if EAT is inducible by a single subset of T cells. Finally, we will determine whether in vitro activated T cells go directly to the thyroid to induce EAT or if they first interact with other cells in the recipient. Since different strains of mice differ in their susceptibility to EAT, the cellular basis for this genetic difference will be examined using this transfer model. In particular, we will determine if genetic resistance to EAT is due to defective antigen presentation to T cells (both in vivo and in vitro steps) and if low responder thyroids are resistant to damage by effector cells. The long-term objective of these studies is to use these basic studies to increase our understanding of the regulatory mechanisms involved in autoimmune disease. When the precise mechanisms underlying the induction of autoimmune diseases are better understood, it should be possible to devise more rational approaches for treating autoimmunity in man.